S212: PHASE I STUDY OF YTB323, A CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELL THERAPY MANUFACTURED USING T-CHARGE™, IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA
Authors: M. Dickinson, M. Kwon, J. Briones, U. Jäger, K. Kato, E. Bachy, D. Blaise, N. Boissel, N. Shah, M Frigault, P. Riedell, L. Shune, T. Teshima, X. Zhu, E. Orlando, L. Yi, J. Davis, E. Bleickardt, I. Flinn, P. Barba, P. Barba
Journal: HemaSphere (2022)

Background: CD19-directed CAR-T cell therapies (tx) demonstrate efficacy in patients (pts) with B-cell malignancies. However, despite positive outcomes with currently approved CAR-T cell tx, many patients fail to respond or relapse after initial response. YTB323 is an autologous CD19-directed CAR-T cell tx generated by the innovative T-Charge™ platform, which demonstrates high potency, preserves T-cell stemness in the final product, and takes <2 d to manufacture. Aims: T-Charge™ is expected to prolong CAR-T cell persistence and yield higher response rates and durability. Methods: These data from the ongoing Phase I, multicenter, dose-escalation study (NCT03960840) focus on safety and efficacy of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Eligible pts had measurable disease at enrollment, ECOG 0-1, and r/r DLBCL after ≥2 lines of prior tx. Pts received single-dose YTB323 at targeted dose levels (DL) 1 (2.5×106 CAR+ cells), DL2 (12.5×106 CAR+ cells), DL3 (25×106 CAR+ cells), or DL4 (40×106 CAR+ cells). Results presented here focus on DL1 and DL2. The primary endpoints are to identify a recommended dose for subsequent trials and characterize the safety and dose-limiting toxicities. Secondary endpoints include overall response rate (ORR) by local investigator assessment and cellular kinetics. Results: As of August 20, 2021, 20 pts with r/r DLBCL received YTB323: 4 at DL1 and 16 at DL2. Median age was 65 y, 65% received 2 prior lines of tx, and 35% had prior SCT. The median follow-up for pts in DL1 and DL2 was 20 and 7 months, respectively. Of 20 pts evaluable for safety, all experienced at least 1 adverse event (AE) of any Grade (Gr) and 80% at least 1 AE Gr ≥3. One pt (25%) experienced Gr 1 cytokine release syndrome (CRS) at DL1, and 5 (31%) pts experienced CRS at DL2, including 4 (25%) Gr 1 or 2 and 1 (6%) Gr 4 (Lee et al, 2014), which met protocol defined DLT criteria at DL2. Tocilizumab and corticosteroids were used for CRS management in 4 (80%) and 2 (40%) pts at DL2, respectively. Median time to CRS onset was 10 d (range, 1-17 d). Five pts (25%) had neurological events (NE), of which the majority were Gr 1. Median time to onset and resolution of NE was 7 and 12 d, respectively. Five pts died on trial (beyond 30 d); 3 pts died due to disease progression (1 at DL1, 2 at DL2), and 1 pt each due to sepsis (1 at DL1) and intestinal hemorrhage (1 at DL2). At DL1, ORR and complete response (CR) rate were both 75%. At DL2, ORR and CR rates were 81% and 75%, respectively. Of the 15 pts who received YTB323 at DL2 at least 3 mo prior to the data cutoff, CR rate at mo 3 was 73% (95% CI, 44.9%-92.2%) (Figure). Median time to peak YTB323 expansion was ~16 d and coincided with cytokine peak. YTB323 expansion (Cmax and AUC0-28d) with 12.5×106 CAR+ cells (DL2) was comparable to a median tisagenlecleucel dose of 312×106 CAR+ cells in pts with DLBCL, a 25-fold lower median dose (Awasthi R, et al. 2020). Limited data indicate that CAR expression was detectable by flow cytometry for at least 9 mo at DL2. T-Charge™ allowed preservation of CD4 and CD8 naive/stem memory T cells in the final product according to flow cytometry. Bulk RNAseq analysis demonstrated that YTB323 retained a naive stem-like gene signature. Image:Summary/Conclusion: YTB323 is a potent new CAR-T cell tx with distinct cellular kinetics, encouraging early efficacy results across DL1 and DL2, and a manageable safety profile. Updated results will be presented at the meeting along with a recommended dose for subsequent trials.